Psychotic Alzheimer\u27s disease is associated with gender-specific tau phosphorylation abnormalities

Converging evidence suggests that psychotic Alzheimer\u27s disease (AD + P) is associated with an acceleration of frontal degeneration, with tau pathology playing a primary role. Previous histopathologic and biomarker studies have specifically implicated tau pathology in this condition. To precisely quantify tau abnormalities in the frontal cortex in AD + P, we used a sensitive biochemical assay of total tau and 4 epitopes of phospho-tau relevant in AD pathology in a postmortem sample of AD + P and AD - P. Samples of superior frontal gyrus from 26 AD subjects without psychosis and 45 AD + P subjects with psychosis were analyzed. Results of enzyme-linked immunosorbent assay demonstrate that AD + P females, but not males, had significantly higher levels of phosphorylated tau in the frontal cortex. In males, but not females, AD + P was associated with the presence of alpha-synuclein pathology. These results support a gender dissociation of pathology in AD + P. The design of future studies aimed at the elucidation of cognitive and/or functional outcomes; regional brain metabolic deficits; or genetic correlates of AD + P should take gender into consideration. (C) 2014 Elsevier Inc. All rights reserved

Assessing time series models for forecasting international migration : lessons from the United Kingdom

Funding: This work was funded by the Migration Advisory Committee (MAC), UK Home Office, under the Home Office Science contract HOS/14/040, and also supported by the ESRC Centre for Population Change grant ES/K007394/1.Migration is one of the most unpredictable demographic processes. The aim of this article is to provide a blueprint for assessing various possible forecasting approaches in order to help safeguard producers and users of official migration statistics against misguided forecasts. To achieve that, we first evaluate the various existing approaches to modelling and forecasting of international migration flows. Subsequently, we present an empirical comparison of ex post performance of various forecasting methods, applied to international migration to and from the United Kingdom. The overarching goal is to assess the uncertainty of forecasts produced by using different forecasting methods, both in terms of their errors (biases) and calibration of uncertainty. The empirical assessment, comparing the results of various forecasting models against past migration estimates, confirms the intuition about weak predictability of migration, but also highlights varying levels of forecast errors for different migration streams. There is no single forecasting approach that would be well suited for different flows. We therefore recommend adopting a tailored approach to forecasts, and applying a risk management framework to their results, taking into account the levels of uncertainty of the individual flows, as well as the differences in their potential societal impact.Publisher PDFPeer reviewe

Pathogenic tau species drive a psychosis-like phenotype in a mouse model of Alzheimer\u27s disease

Psychotic Alzheimer\u27s disease (AD + P) is a rapidly progressive variant of AD associated with an increased burden of frontal tau pathology that affects up to 50% of those with AD, and is observed more commonly in females. To date, there are no safe and effective medication interventions with an indication for treatment in this condition, and there has been only very limited exploration of potential animal models for preclinical drug development. Pathogenic tau is over represented in the frontal cortex in AD + P, especially in females. In order to develop a candidate animal model of AD + P, we employed a tau mouse model with a heavy burden of frontal tau pathology, the rTg(tauP301L)4510 mouse, hereafter termed rTg4510. We explored deficits of prepulse inhibition of acoustic startle (PPI), a model of psychosis in rodents, and the correlation between pathogenic phospho-tau species associated with AD + P and PPI deficits in female mice. We found that female rTg4510 mice exhibit increasing PPI deficits relative to littermate controls from 4.5 to 5.5 months of age, and that these deficits are driven by insoluble fractions of the phospho-tau species pSer396/404, pSer202, and pThr231 found to be associated with human AD + P. This preliminary data suggests the utility of the rTg4510 mouse as a candidate disease model of human female AD + P. Further work expanded to include both genders and other behavioral outcome measures relevant to AD + P is necessary. (C) 2014 Elsevier B.V. All rights reserved